9-beta-hydrogen-11-keto steroids



United States Patent Ofiicc 9-BETA-HYDROGEN-11-KETO STEROIDS Ewart Ray Herbert Jones, Harold Bernard Henbest, and Gilbert Frederick Woods, Manchester, David Ernest Hathway, Wembley, and Gordon Haydn Thomas, Ac- 7 ton, London, England, assignors to Glaxo Laboratories Limited, Greenford, England, a British company No Drawing. Application May 21, 1953 Serial No. 356,906 Claims priority, application Great Britain May 22, 1952 19 Claims. Cl. 260-3972) This invention is concerned with improvements in or relating to the preparation of steroid substances of a novel-type, the structural characteristics of which essentially' comprise a fi-hydroxy or esterified B-hydroxy group in the 3-position, an a-hydrogen atom or u-hydroxy or a-acyloxy group in the 5-position, a hydrogen atom in the isoor B-configuration in the 9-position and a keto group in the ll-position.

Very few steroids have hitherto been described, as far as we can ascertain in which the hydrogen atom in the 9- position has the B-configuration and indeed the type of reaction by which we have found our new compounds can be prepared is also novel, The configuration of the 9-hydrogen atom is proved by the fact that it can be made to revert to the normal configuration by treatment with alkali as described below. While it is extremely difficult to obtain evidence on the point we believe the configuration at position 8 is natural.

The structural characteristics of the said new steroids will be apparent from the following schematic representa- R2 where R is a hydroxy or esterified hydroxy group (in the [3-position) R is an a-hydrogen atom or an a-hydroxy or a-acyloxy group and R is a side chain substituent, the nature of which will be described hereinafter.

The herein described new steroids are we believe, generally useful in the production of ll-oxygenated steroids and several members of the new class are valuable intermediates in the synthesis of cortisone in that they can readily be prepared as hereinafter described and can be converted to cortisone by known procedures once the configuration of the 9-position has been reversed by a method to be described later in this application. Thus after reversal of the 9-hydrogen, degradation of the side chain and elaboration of the 3-keto-A -system can be readily effected.

For example, 3fl-acetoxy-11-keto-9B-ergost-22-ene, one of the new compounds of this application, can be treated with strong alkali, as will be described hereinafter, and converted to 3fl-acetoxy-11-keto ergost-22-ene having the normal configuration at the 9-position. According to the procedure outlined in Chamberlin et al., J. Amer. Chem. Soc., 1951, 73, 2396, this last mentioned steroid compound can readily be converted to 3B-acetoxy-11z20-diketoallopregnane and this compound can in turn be converted to cortisone by procedures outlined in Tishler et al., J. Amer. Chem. Soc., 1951, 73, 4052, and Rosenkranz et al., Nature, 1951, 168, 28.

As stated above the new steroids can be prepared by a reaction which we believe of itself to be novel and which comprises the hydrogenation of such steroids as have a p-hydroxy or esterified p-hydroxy group in the 3-posi- 2,891,213 Patented July 2 mm, ahydmgm atom or a-hydroiy or a-acyloly group in the 5-position, a double bond in the 7-position, a keto group in the ll-position, the 9-hydrogen atom of which has the B-configuration; steroids of this last-mentioned type may be schematically represented as follows:

1'2 7 m where R R and R have the above-stated meanings. It is to be noted that hydrogenation of a A' -double bond in a steroid having the normal configuration at the 9 position produces migration of a 7:8-double-bond to the 8 :9- or 8: 14-positions. This fact has also hitherto proved an obstacle in steroid chemistry and in particular in the synthesis of cortisone, in that the reduction of most compounds having 8:9- and 8:14-double-bonds is not easily effected. In contrast the reduction of the A -double bond in the preparation of our new compounds proceeds easily and smoothly. This curious behaviour can, we presume be attributed to the particular structural characteristics of the starting material at the 9-position.

Accordingly the invention comprises as new compounds, such steroids as have a fi-hydroxy or esterified p-hydrox y group in the 3-position, an a-hydrogen atom or an ahydroxy or u-acyloxy group in the 5-position and a keto group in the ll-position, the hydrogen atom in the 9- position having a fi-configuration. I In that the herein described new type of compound is of particular value in the synthesis of cortisone the invention specifically includes such of the new class of steroid as haveone of the following side-chains in the 17-position:

since such side-chains are easily degraded or converted into the cortisone side-chain; we find compounds having side-chain No. 2 (where X is bromine) to be particularly: valuable. We also prefer such compounds as have an acyloxy group in the 3 8-position particularly an acetyloxy group, and an a-hydrogen atom or an a-hYdIOXY or a-. acyloxy (erg. acetyloxy group) in the 5-position.

For the purposes of illustration the following are'the characteristics of two specific and preferred compounds within the said new class:

3 ,8-acetoxy-22 23-dibromo-l 1-keto-9 3-ergostane M.P.=226-230 C. I [oz] =+30 (c. 1.0 in chloroform) Bil-acetoxy-ll-keto-9 8-ergost-22-ene V M.P.'=170l73 C. [a]n=,-l-20 (c. 1.0 in chloroform) t be. understood. hatv he.v foregoin Qharaeteristi s were determined for the pip-est material we have been able to obtain and may be liable to variation dependent on he PR X t an -Part cu a samp ed the empqhad mq e tien- [Acc rd ng-to a e t re o he a e tiea h hereinidese ibe new t roids a e p epa e seeete y ie y y ene insi ue t tereids: ee aye ah-h dt ay e e fied hydroxy group in the 3,-position, a hydrogen atom or an a-hYdIOXY or; wacyloxy group in the -position, a double bond in the, 7-position and a keto group in the ll-position (the hydrogen atom in the 9-position having the B-configuration) in'the presence-of an inert organic solvent.

We prefer to effect the herein describedg'reaction on such starting materials as have the specific side-chains 1-6 liereinbefore referred to; it, should however be noted that the-hydrogenation conditions ofthe reaction may cause. reduction o'freducible groups in the side chain and that a. protectedb typeof 'side-chain'is advantageous; thus. to obtain A compounds we prefer to hydrogenate cornhaving side-chains ofthe type No. 2,and then to dhaljogenate the-resulting compound for exampleby treatnient zinc and acetic acid.

The. catalyst employed-may be any of 'the normal catalysts 'employed ini eactions involving the hydrogenation. of'double-bonds such as platinum, and'pall-adiumgcatalysts and preferred examples are Adams platinum oxide andpall'ladised'charcoal.

The solvent employed should" of course; be inert under the prevailingreaction conditions and asuitable solvent is'g'la'cial acetic acid; either alone 'or admixedwith dioxan r. qme pi The reaction is conveniently-effected at room temperature for example by shaking a solution of the starting material an atmosphere of: hydrogen. The optimum pressure for thereaction appearsto Varyaccording tothe. nature ofthe starting material' and can be deterntined' by. l m er w e e.

we have' foundthat the starting materials used in the process according to the invention can conveniently'be prepared by the action of a Lewis acid on steroids having/ e fiy r esterifie -fieh erean ro p the -p tion, an a-hydrogen atom, or an a-hydroxyl or a-acyloxy group in the 5-position, aj7:8-double bondand an oxidebridge between,- the.,9-;. andv l-lepqsitions carebeing taken to p the resets a he PPmPri e mee Heusser et a1. (Helv. ChimfAclta, 1951, 34, 2106) have described the preparation of compounds which are similar to those of Formula II above, -but.which have the double bond in heflfi)1msitiqm mteadi fii h flvnesiti fr m compounds the'essential featuresof which may be sche: matically represented as follows:

4 which. as. formed was, quickly conver ed to the Aw type of compound.

It will be observed that as the reaction proceeds the optical rotation drops until a is reached which corresponds to the quantity; of ll-dfietQrAfi-Qflsteroid. lflthereactien; allowed to proceed further the latter compound is rearranged; to. form a A -l1 ketone and rotation again increases during such rearrange meat. The. reaction sho ld: therefore he. stopped at the stage when; the. optical; rotation-ofz the reaction mixture reaches a. stated. above the. reaction according to the invention is inclined: to proceed rather p y makiueihdifiieultto stop: it at; the.- r q stage; it should therefore be. slowed down either by the use of only small; quantities of the, Lewis acid or by suitablechoice of, solvent as. hereinafter described. The reaction, may. be stopped for example by quenchingwith. wate r pyri ne.

According to a further feature ofthe invention there.- fore,ywe provide a process. for the preparation of. the starting materials for the. process according to the. invention, in which a 3B -hydroxy (or esterifiedr hydroigyl-A' 9:1'1-oxido steroid which may or may not have a hydroxy. or acy loxy group in the 5,p osition, is reacted in an. inert organicsolvent with, a Lewis acid,,as -hereinafter defined, the reaction 'being stopped'at the, stagewhere, the optical rotation of the. reactionmixturereaches a: minimum.-

The erm,Lewis ci as.- se.d. herein-has he. mea generally assigned. to it in.theuart,.. at this time, namely; a substancerwhich is capable of acting as. an electron: a cep o or atI a tIWQeIe mn he term. does not. of course include anyv substance which. is v itself-f capable. of, dissociation with the formation. ofjhydrog env ions. An exp ana on of the te ewisa idf may befor example be ,found onpage, 80, of Advanced, Organic. Chemistry? by Wheland, 2nd edition, published by John Wiley & Sons Inc, New York.

Preferred exampleof. Lewis acids for the herein described process are boron triflujoride (conveniently used as its etherate) and stanniechloride.

As stated above it isimportant to slow the reaction as much as possible so that it may be stopped at the desired point. While any inert organiesolvent'may be used in the process we have found that-the-speed of the reaction is greatly influenced by the nature of such solvent. Thus inbenzene the'reactiomtake s place 'very rapidly while'in ether it 'is much-sl'owert'we therefore prefer toemploy an aliphatic etheras the solvent for; examplediethylether or tetrahydrofuran.

'Fhe rate ofreaction-is also influenced'by the quantity of Lewis acid"-employed andifgthe reaction isproceed ing too'quick-ly nnder giveniconditions it can be slowed by using less Iiewis acid: We prefer to employ from 05 1 to '1'.5'molso f. the "I: 'eW is acidper mol'o fystarting material: Theprocess/is conveniently carried" out, at

temperatures whithin the'range 'of' from 40 to t l- C.

We have found'further that theqconfigpra'tion of'the Q-hydrogen 7 atom the; new hydrogenated compounds according to the invention can be reversed to..give the normal, 9u configura tion. We have foundithat thisinversion may be; etfected' by subjecting thenew compounds according tonthe;invention to a treatmentwith alkali'so as to cause ionisation o f the 9-hydrogeuatom (pre umably y sonof eto-enol" tau omerism attire '1 eketo roup) nd r wh ch. 7 onditions the 9- ydrogen, tom. s obse d; o revert its. norm l nfiguration. Thi n e si.on sl e mpaniedby. a hainem thel p otat on. whieh fea ime. eaun elfii hz mp oyed to, com

ro g err t on. Thu the otationof the. 9aecompoundsi sm re. n gative han h ot hefifiompounds.

' In using this characteristidtoldetermine,whatcondi: ita s.aret ui abl rea eshould be akefir o, asethe com-' parison. 1 ompounds i h. hy roxyt o p in he. 3: nd i-p si ionst nd idehainsiu the. 1'7.-p0. i i n;whih. wilhno e afieetedt. l usjwe havetfoundthat strongg alkaline conditions are required to effect the desired inversion and whether any given conditions are sufficiently strong can be determined by observing whether the rotation becomes more negative. The conditions of the process will of course, saponify any ester groups in the 3- or 5-positions and thus 3 and/or 5-esters are not obtained by this process. If 3- and/or 5-esters are required, these may be obtained by re-esterification.

According to a still further feature of the present invention, therefore, we provide a process for the preparation of steroid substances, whose nucleus may be represented by the following general formula,

1 (In) in which the new compounds according to the invention are subjected to strong alkaline conditions.

We prefer to achieve the strong alkaline conditions required by the use of alkali metal hydroxides, such as sodium or potassium hydroxide in alcoholic or aqueous alcoholic solution or alkali metal alkoxides in alcoholic solution or in suspension in an inert solvent such as ether or benzene. A 15% w./v. solution of potassium hydroxide in ethanol has, for example, proved to be convenient.

The reaction is conveniently carried out at a temperature within the range of from 200 C. preferably by boiling a mixture of the reactants. The time required for the process depends on the temperature employed and completion of the reaction can be determined by determining when the rotation ceases to become more negative.

It must of course be remembered that some C sidechains will be sensitive to the conditions of the process according to the invention while otherwise suitable for easy conversion to the cortisone side-chain. In such cases they can be protected in known manner. Thus while in preceding stages we have found 22:23-dibromoergostane derivatives to be especially convenient, for the present process the bromine should previously be removed, for example by treatment with zinc and glacial acetic acid.

In order that the invention may be well understood the following examples are given by way of illustration only:

A. PREPARATION OF COMPOUNDS OF FORMULA I Example 1 V Hydrogenation of 3fi-acet0xy-11-ket0-9Bergosta-7:22- diene-36-acetoxy-l1-keto-9B-ergosta-7 :22-diene (4.596

g.) was dissolved in acetic acid (300 ml.) and the solution shaken with Adams catalyst (508 mg.) in an atmosphere of hydrogen for 15 minutes. Two mole. equivalent of hydrogen was absorbed in ca. 5 minutes, after which no more hydrogen Was taken up. After filtration, the solution was evaporated to dryness in vacuo and the residue crystallised from methanol. 3B-acetoxy-11-keto- 9p-ergostane (4.020 g.) separated as rods, M.P. 150- 151, [al +45 (c., 1.0 in chloroform). (Found: C, 78.60; H, 11.10. C H O required C, 78.55; H, 10.99%.) A mixture of this compound and 3fl-acetoxyll-keto-ergostane melted at 116121. spectrum showed bands at 1735 and 1235 cm. (acetoxy groups, 1720 cm.- (unconjugated carbonyl). The compound had negligible absorption in the U.V. above 200 Example 2 i (a) Hydrogenation of .ifl-acetoxy-ZZ 23-dibr0m0-11- keto-9p-ergost-.7-ene.3p acetoxy 22:23 dibromo 1 1' The infra-red keto-9fl-ertgost-7-ene (5 g.) in chloroform (50 ml.) andacetic acid (100 ml.) were shaken with Adams catalyst (1 g.) in an atmosphere of hydrogen until one, mole. equivalent of hydrogen was absorbed (ca. one hour). After filtration, the solution was evaporated to dryness in vacuo and the residue crystallised from ethyl acetate. 3B-acetoxy-22:23-dibromo-11-keto-9B-ergostane (2.7 g.) was obtained as rectangular plates, M.P. 226-230 [0:1 +30 (c., 1.0 in chloroform.) (Found: C, 58.6; H, 8.0. C H O Br required C, 58.4; H, 7.9%.) The infrared spectrum showed bands at 1735 and 1235 cm." (acetoxy group) and 1725 cm:- (unconjugated carbonyl). The compound had negligible absorption in the U.V. above 220 m (b) Debromination of 3B-acet0xy-22 23-dibr0m0-11- ket0-9/3-ergostane.-3p-acetoxy-22:23-dibromo ll-keto- 9fl-ergostane (2 g.) in chloroform (40 ml.) and acetic acid ml.) was stirred at room temperature with zinc dust (10 g.) for 2 hours. The solution was filtered and diluted with water (200 ml.). The chloroform layer (diluted to ml.) was washed with water (100 ml.), saturated aqueous sodium bicarbonate (100 ml.) and water (2 x 100 ml.) and then evaporated to dryness. Crystallisation of the residue from methanol aiforded 3,6 acetoxy-l1-keto-9fl-ergost-22-ene (1.2 g.) as plates, M.P. 170-173", [al +20 (c., 1.0 in chloroform). (Found: C, H, 10.64. (3301 14 03 required C, H, 10.60%.) Bands were found in the infra-red spectrum at 1735 and 1240 cm." (acetoxy group), 1715 cm.- (unconjugated carbonyl) and at 970 cm. (side chain double bond).

Example 3 3,8:5a diacetoxy 11 keto 9,8 erg0stane.3fl:5a diacetoxy 11 keto 9/8 ergosta 7:22 diene (4 g.) acetone solvate was dissolved in acetic acid (500 ml.) and the solution shaken with Adams catalyst (400 mg.) in an atmosphere of hydrogen. Two molecular equivalents of hydrogen were absorbed in 10 minutes. After filtration, the solution was evaporated to dryness in vacuo and the residue crystallised from methanol when 3,3:5a-diacetoxy-11-keto-9B-ergostane (3 g.) was obtained as plates, M.P. 127-130; [a1 +62 (c., 1.0% in chloroform). The compound had only slight general absorption in the U.V. above 200 m The infra-red spectrum in CS showed bands at 1735 and 1236 cm.- (acetoxy groups) and at 1725 cm. (unconjugated carbonyl). (Found: C, 74.25; H, 9.87. C H O requires C, 74.40; H, 10.1%.)

Example 4 3n acetoxy 5a hydroxy 11 keto 9p bisnorallocholanic acid methyl ester.3fi acetoxy 5a. hy droxy 11 ketobisnorallochol 7 enic acid methyl ester (200 mg.) in glacial acetic acid (1.5 ml;) was shaken vigorously with a platinum catalyst (20 mg. PtO prereduced in 0.5 ml. AcOH) in an atmosphere of hy-. drogen. The rapid uptake of hydrogen ceased after 12 minutes when precisely the equivalent of one molecule. had been absorbed. The platinum was filtered and the filtrate evaporated under reduced pressure to a rapidly crystallising clear gum. Recrystallisation from methanolyielded 35 acetoxy 5 hydroxy 11 keto 9/3 bis norallocholanic acid methyl ester as plates mg), M.P. 187; [061 +84.4. (Found: C, 69.45; H, 8.87. C H O requires C, 69.12; H, 8.75%.) Light absorption: absorption at 207.5 mg.

El? 13.9 (0., 0.0175 EtOH Infra-red absorption showed bands at 3420 cm." (by- B. PREPARATION OF COMPOUNDS OF FORMULA II V Example 5 3,8 acetoxy 22:23 dib romo 1 1 -'k e t0 973 {erg arson-era 7 7" -fIlB.-f 3;9 acetoxy 22-523 "dibromo 9a! 1 1a epoxy ergdsh 7 ene (2g.) :dissolved in dry ethyl ether (2'00 nilf wastreated boron trifluoride ether complex (0.8'2 ml.; 2 equivsl'). lxfter'standing at room temperaturefor "3V2 hours the crystalline solid which had separated was collected (0. 93 g.), 194-196; {ab I20. The ether filtrate was concentrated -at room temperature "to half "its volume and a "further batch 'of so'lid3cllected-("0f3 g.) [uh --'1'I7. 'The two batches of solid were recrystallised frornethyl acetate to yield the ke'tone (1. g.) as colourless needles, 'M.P. 194-196", [e51 ,--122 (e.,30;infCHCl (Found: C, 5819; H, 75. "C fiHgQgBr requires' c, "5817; *H, 7.5. Light absorption: General absorption Eli... at 250 m,t=;m'

v :Example '6 373 acetoxy- 22:23 dibromo 9a:'1'-1a epoxyergost 7"--'en'e"( l g.) dissolved in dry benzene (25 ml.) Was-treated with boron trifluor'ide-ether complex (0.2 ml.; 1 equiv) After standing at room temperature for one minutethe mixture *was shaken *vigorously with water. The benzene solution was washed with aqueous sodium bicarbonate *and water and the solvent-evaporated. The residue was recrystallised from "ethyl acetate to yield impure ketone=(0;4 'g.-),='M.-P. 180-181, Loll -1'13".

.Example'7 35- llceloxy --1 1 keto --9j3 -el.'g0sta -.7:22 diene.- 3 3 'acetoxy -9: l1 -:epoxyergosta 7:22 :diene (2.5 g., dried for 3 hours at 100 in a high vacuum), was dissolved in dry distilled :benzene (60 cc.) and treated rapidly at .20 with freshly distilled boron trifluoride etherate (10 drops, 0.133 g.). The solution immediately went brown ianditheireaetion wasstopped after 1 minute by quenching with water. The benzene solution was washed;three-times with water, twice with sodium bicarbonatesolution, twice more with water and then dried. The zsolution was evaporated to dryness and the residue crystallised from acetone giving .3fl-acetoxy-11-keto-95- ergosta-7r22 diene (1.95 g.; 78% yield) as elongated prisms, M.P. 157-1599, .[aJ -1 86.3 (c., 2.27) (in chloroform). .After two further crystallisations the MiPswas constantiat 159-1619, [111 190.5 (0., 1.16,). (Found: C, 79.45; 1H, 10.4; G ol-T 0 requires C, 79.25; H, 10.-2% .Light absorption inalcohol: max. 295.0 A., e=-1 00.

Example 8 3/3 acetoxy 11 ket0*- 9fi"--erg0sta 7:22 diene.- Freshly distilled boron 'trifluoride etherate '(6 .ml.) was added to alsolutionof .3,9=acetoxy-9:1la-epoxyergosta 7z22 diene:(-l9 g!) in dry ether (.2 1.'). The solution was left'forrl6 hourszatzroomutemperature and then washed with water (300 :m'l. saturated aqueoussodium bicarbonate (23c 300zml.) and water (300 m1). Afterrough drying'wvith' m'agnesiumsulphate, the solution was evaporated to dryness leaving r3 3-acetoxy-l1+keto-9fi-ergosta- 7 :22 diene (-l8f5 g.'), M.P..l47-:l'51, [M 18l. On crystallisation from methanol the :B'y-unsaturated ketone (17 g.) was 'obtained .as"pla'tes, .M.P. 150-152, [0th, 486".

Example .9

3,8551; Ziiacetoxy 11 keto 95 ergosta 7:22 diene.A solution of 3'flz5a-diacetoxy 9z ll-epoxyergo'sta- 7:22-diene (10 g.) in a mixture of dry benzene (150 ml.) and dry ether 350'ml.) was stored-atroom temperature with boron Itrifluoride etherate (5 ml.) -for 3 .hours. After'was'hing.the'solution With'water.(3 x-200'ml.) and roughly dryingiwith magnesium sulphate, :it was evaporated to -.dryness below 50"'/-l2.mm. The "residual oil, which slowly solidified, was :crystallised from aqueous acetone. The crystals were collected and dried at 100/ 12 mm. for 2 hours 'when' 3flz5a-diacetoxy-l l-keto- 9fliergosta 7z22 diene (8551.) was 'obtained with Mi-P.

140- 143, EwJ --49" -"(e., 1.0% in chloroform). (Found: 0,7 1.75, H, 9149. 'C H 0 requires C, 74595 H, 9-.43%) r X259} 20'8 m flog e 3.68

. Example 10 3,8 -'aceroxy 5a hydroxy 11 'ke'to 978 ergost 7:22 'diene. B-acetoxy-5whydroxy 9a: l'la epoxyergosta 7'f22-diene (2515 g.*) dissolved in 'pure :sodhim benzene (T5 nil.) "was treated with freshly-'distilledhoron trifluoride etherate 24--'drops 20.32 g.'-). "The solution was allowed tostand for IOniinu-t'es at room-temperature, then shaken well with sodium bicarbonate solution. The benzene layer was washed well with water, dried over anhydrous sodium sulphate and evaporated to dryness. The residue recrystallised from tacetone, gave 1.62 g. of 3 ,B-acetoxy-S a-hydroxy-l l-keto-9B-ergosta-7 22-diene, as plates, M.P. 174-483, [ab 1l2 (CI-ICl c.=l.06).

.A sample recrystallised for analysi'sfrom acetone had M.P. 181-18 7", [m --135-.(c.=-1.33.). UN. absorption maximum 29-10 A.: 2: 1-90. (Found: C, 763; H, 9.9%. 0 11 0.; -:requires.C, 76.55.; H, 9.85%.)

Example 11 3/S-acet0xy-5a-hydroxy-I1-keto9fi-bisnoralloehol 7-enic acid methyl 'ester.3fi-acetoxy-5a-hydroxy 9:l'l-oxido bisnorallochol-7-enic acid methylester (500 mg) in dry benzene ,(50 mli) was treated with boron .trifluorideether complex '(5 drops) and allowed 'to stand 5 minutes. It was then washed with sodium bicarbonate solution, water, dried and evaporated. The solid product was recrystallised'rfrom methanol. Small ro'd like needles of 3p acetoxy 5m hydroxy 11 keto -9B bisnoral 1och0l 7-enic acid methyl .ester (300 mg.), '169 I702, were obtained. Recrystallisa'tion from methanol gave needles M.P. 171-2", "M15 --109 "(1197 'in CHCI Lightabsorption: A max..206.5 m

.Efi (0 0004528 in .EtOH) Infrared absorption shows "bands at 3520 =cm.'-- (hy' droxy); 1735 and "1242 'cmz-" '(a'cetyl); 1708 cm?" (carbonyl); 1166 cm. -('ester);-807 and '840"cm.'-- (=Iiisubstituted 'double bond). Analysis.iFounilz"C, 69.53; H, 832 9; C H gO Tequires (3, 69.42; 11,8539.

Example 12 The following experiments were carried out ;to.-.den:ronstrateithezdropin rotation aszreactioncprocee'ds:

1(a) .Jh'e'paration 0].533:JQHdiacemxyJJ+ket0;9;is0erg0sta-7z22-diene (Table I ).-Stannic chloride (0.3 ml.) was added to dryether (35.ml-). The white crystalline pre cipitate of the 's'tannic chloridele'ther complex was dissolved by adding drybenzene. To this solution at 20 was added 3pz5ot-diacetoxy 9zl l-oxidoergosta-7:22-diene (2 g) :disso'lved in'adry tether 1 (:30 g. The rmixture'was at 'first too turbid .f0i10WY1h81I63LGfi011ZbY meanszo'f itsoptical I rotation, but afs'imilari solutionpreparedwvithout etannic chloride had a-ihigh positive rotation. -After 5=minutes-the-solution h'a'cleleared and the rotation' had fallen to a negative value. After 2 60 minutes .the "rotation of" the solution reached a maximum negative value, and thereafter becameslowlymore-positive. The change inrotation with time istabulated in 'TziblefI.

TABLE I Time 102]!) Decrees (b) 3 B-acetoxy-ZZ :23-dibrom0-11-keto-9fl-erg0st-7-ene in chloroform (Table Il).- The epoxide (2 g.) was dis solved in chloroform (65ml) and boron trifluorideether complex (18 drops) added. The rotations after crystals 1.0 g.) M.P. 217-2247, [041 "-44.2.

TABLE II 'Ilme [aha De reea in .3m; -s4.:: 9 mins -35. 3 12 n: 35. 3 15 wins. 34. 2 18 ruins- --33. 2 33 mins -30 63 mins- -28 153 mins 17 (c) In tetrahydrofuran (Table IIl).-The above epoxide '(5 g.) dissolved intetrahydrofuran (150 ml.) was treated with boron trifluoride-ethencomplex (1.65 ml.). The change of rotation with. time'was determined on standing at room temperature and is shown in Table III. In a second experiment after standing at room temperature from one hour, the product was isolated in the usual way. On crystallisation from acetone a solid (2.15 g.) was obtained, M.P. 183-l87; [al ---107.

(d) Erample 5 was repeated and change in rotation of the reaction mixture with time was determlned the results are shown in Table IV.

TABLE IV Time [01]!) Degrees n -3 6 mins 9. 8 10 minq -16. 3 20 mine -22. 2 40 m 38 60 mine -45 80 mins -53 100 m 57 1201mm --57 Example 13 3B acetoxy 22:23 -'dibr0m0 95 --ergost 7 en 7 11: one.-(a) A solution of 3fi acetdxy-22 z23-dibromo- 9azlla-epoxyergost-7-ene (Budziarek et al., 1.0.8., 1952, 3410) (50 g.) in toluene (1.5 l.) was concentrated to 1 litre at atmospheric pressure. After precautions were taken to prevent ingress of moisture, the solution was treated with freshly distilled boron trifluoride-etherate (10 ml.; 11 mol.) for minutes at '35. Pyridine ml.) was then added to the solution, which, after warming to room temperature, was washed successively with water, aqueous sodium bicarbonate, and water, and concentratedin vacuo ,to 200.ml.; needle s -(41 g.;- rm separate. T in get-12 mm crystallisation from benzene afiorded the ll-ketone as needles, M.P. 196-198 [M -.123". (Found: C, 58.6; H, 7.65. C30H46O3BI'2 I'Bqllil'fis C, H, The compound showed no selective absorption of high intensity above 220 m. Infra-red spectrum (in CS peaks at 1735 and 1235 (acetate), 1730 (ll-ketone), 1654, 821, and 805 cm.- (trisubstituted nuclear double bond).

C. PREPARATION OF COMPOUNDS OF FOR- MULA HI I Example 14 Rearrangement of 3,8-acetoxy-11-keto-9fl-ergostane- 3B-acetoxy-11-keto-9fl-ergostane (1 g.) and potassium hydroxide (7.5 g.) were heated in refluxing ethanol (50 ml.) for 18 hours. The solution was diluted with water (300 ml.) and extracted with ether (2 x ml.). The combined ether extracts were washed with water (3 x 100 ml.) roughly dried with magnesium sulphate and evaporated to dryness. The residue was reacetylated by treatment with refluxing acetic anhydride (20 ml.) for minutes. Evaporation of the solution to dryness in vacuo followed by crystallisation from aqueous methanol afiorded 3-acetoxy-ll-ketoergostane (0.7-8 g.) as needles, M.P. 135136, [a] =|-33. Heusser et al., Helv. Chim. Acta, 1951, 256, 2123, gives M.P. 135- 136 [a] =+32). (Found: C, 78.50; H, 10.95. C H O calculated C, 78.55; H, 10.99%.) Mixed melting point with authentic 3fi-acetoxy-1l-ketoergostane, obtained by catalytic reduction of 3fl-acetoxy-11-ketoergost-22-ene, was undepressed. The infra-red spectrum was identical with the infra-red spectrum of an authentic specimen of 3fi-acetoxy-1l-ketoergostane.

Example 15 Rearrangement of 3 acetoxy 11 keto 9p ergost- 22-ene.A solution of Bfi-acetoxy-l l-keto-9fi-ergost-22- ene (1 g.) in ethanol (50 ml.) was heated under reflux with potassium hydroxide (7.5 g.) for 20 hours. The solution was diluted with water (200 ml.) and extracted with ether (2 x 100 ml.). The combined ether extracts were evaporated to dryness and the residue acetylated by heating with acetic anhydride for 20 minutes under reflux. Evaporation of the solvent in vacuo followed by crystallisation of the residue from aqueous methanol, afforded Sfl-acetoxy-ll-ketoergost-ZZ-ene (0.85 g.) as laths, M.P. 121-124", [a1 +13. Heusser et -a1., loc. cit., give M.P. 125126, [el +125). Found: C, 79.27; H, 10.62. C I-I O requires C, 78.89; H, 10.60%.) The melting point was undepressed onadmixture with an authentic specimen of 3p-acetoxy-11- ketoergost-22-ene. The infra-red spectrum of the compound was identical with that of authentic BB-acetoxy- 11-ketoergost-22-ene. 1

Example 16 chloroform). (Found: C. 77.5; H, 10.9. C H O requires C, 77.7; H, 11.2.)

I 7 Example 17 3B acetoxy 5 hydroxy 11 ketobisnorallocholanic acid methyl ester.3fl-acetoxy-5ahydroxy-11-keto-9fibisnorallocholanic acid methyl ester (500 mg.) in ethanol (25 ml.) containing potassium hydroxide (15%) was refluxed for 15 hours under nitrogen. After dilution with brine and extraction with ether, the aqueous layer sadidified -(HG1 and the liberated acid extracted with ether. 'Fhe ether solution'was washed with water, dried and evaporated {01116 :pdint 'of-crystallisation (50 Diazomethane in ether (prepared from 0.5 "g. nitrosome'thyl urea' was then added and the solution steod ior' 2 'hou'rs' at room temperature. On evaporation to "dryness the =so'lid residue was taken up in acetic anhydride (25 ml.) and the solution refluxed /2 hour. Evaporation -of .the fill-hYdl'ide left a white crystalline residue which on crystallisation from methanol yielded 313 acetoxy oz hydroxy I1 ketobisnorallocholanic acid methyl ester (135 :mgs) M.P. 215-18, [(11 5-185 (e,, 05501-101 Lightiabsorption: slight max. 205 I L r Eifian 8-(c 0.005.5E12OH) Infra-red absorption showed bands at 3600 -cm;-- (hy= droxyl), W732 and 1236 CHI-"'1 (acetate), 1700 cm:- '(-unconjugated'carbonyl); 1735 and 1-156 cm? (ester). Ar'z'alysis.'Found: C, 69:44; H, 8.92. C 5H O requires C; 6912; H, 8. 75.

1. A steroid compound having'the general'formula V :11 whereA. is selected ,from the, group-.consisting of ,arsiugle bond and a double\bo1id,v R :is n-memberrof-the group consisting of a hydrogen atom, a hydroxy group and an 'acetoxy group and R is van -organic radical selected from t ts oup c a 1GB; .CIJHS -oHoH=oH-cH--orr c-m),

where'R isamemberof the ;:group consisting of a-hydroxy group and an acyloxy group 'derivedfrom a lower alkyl-carboxylic acid, R 'is 'a member of ,the group consisting of a hydrogen atom, a hydroxy group and an acyloxy group derived from a lower carboxylic acid, R is an organic radicalsel'ected from the group consistingrof v 1 2 on, crr, om" -rdn-rooone-on-ooon ,413-0110 and GO-CH 'where "X isahailogenselected from the group consisting df :chlorine and homine and R is a member of the group "consisting of hydrogen and 'a lower ;alky1 group, "and where the dot at the 9-position signifies the presence ofajB-hydrogenatom, comprising catalytically hydrogenating inzthe presence of an inert solvent asteroid eompoundhaving'the general formula where R1,"R3 end -R -havethe same meaning as above.

:8. A processlaslclaimedinc1aim'7;"in whichthe hyrdrogenationcatalystjs -aJnemberselectedirom thegmup consisting ;of ,platinum I oxide and .palladised charcoal.

9;. A .proeess asnolnimedjiniclaim 7,.in which the inert organic ..solvent,comprises aactic .ncid.

10. A,pr ocess .as claimed .in claim .7,,in whichn solution of the starting material v.in ..the'jinert organic. solvent is shaken .in )the presence of "the fhydrogeneration catalyst in an .atmosphere \oflhydrogen :atroom iemper-ature.

.1 1. A ,processior .the preparation rofla compound having the generalformula :and WIiI'QCXY is oihiflbgi Selected from 1116 group consisting -ofchlorine and bromine aud -R 33 member of thegmup consisting of' hydrogen and alower alkyl group, and Where the dot at the 9-positi oh signifies the presence of a fl-hydrogen "atom, comprising reacting in athe presence of :an inert crganic ,SOlYfilltzfi-COIH' poundrhavingihe generalzformula 1 v Wh re R JP-"and? R 31mm i'same as above WIth -aLewis ecid'nnd stoppingthe'reaction "at "the stage where the optical rotation of the reaction mixture reaches a minimum.

12. A process as claimed in claim 11, in which the Lewis acid is a member of the group consisting of boron trifluoride and stannic chloride.

13. A process as claimed in claim 11, in which from 0.1 to 1.5 mole of Lewis acid are used per mol of starting material.

14. A process as claimed in claim 11, in which the inert organic solvent is an aliphatic ether.

15. A process as claimed in claim 14, in which the aliphatic ether is selected from the group consisting of diethyl ether and tetrahydrofuran.

16. A process as claimed in claim 11, in which the reaction is carried out at temperatures within the range of from -40 to +40 C.

17. A process of converting to the rat-configuration a 9,B-hydrogen atom of a steroid compound having the general formula o=f R O I 1 where R is a member of the group consisting of a hydroxy group and an acyloxy group derived from a lower alkyl carboxylic acid; R is a member of the group consisting of a hydrogen atom, a hydroxy group and an acyloxy group derived from a lower alkyl carboxylic consisting of and --CHCH where X is a halogen selected from the group consisting of chlorine and bromine and R is a member of the group consisting of hydrogen and a lower alkyl group and where the dot at the 9-position signifies the presence of a fl-hydrogen atom, comprising subjecting said steroid compound to strong alkaline conditions.

18. A process as claimed in claim 17, in which the strong alkaline conditions are obtained by the use of an alkaline material selected from the group consisting of alkali metal hydroxides and alkali metal alkoxides, said alkaline material being dissolved in a solvent selected from the group consisting of an alcohol and a mixture of alcohol and water.

19. A process as claimed in claim 18 in which said alkaline material is an alkali metal hydroxide.

References Cited in the file of this patent UNITED STATES PATENTS 2,345,711 Marker Apr. 4, 1944 2,492,188 Sarett Dec. 27, 1949 2,798,082 Chemerda et a1. July 2, 1957 2,837,514 Chamberlin June 3, 1958 

1. A STEROID COMPOUND HAVING THE GENERAL FORMULA 